Controlling coccidiosis in poultry with 1,4-naphthoquinones



United States Patent Ofifice 3,367,830 Patented Feb. 6, 1968 3,367,830 CONTROLLING COCCIDIOSIS IN POULTRY WITH 1,4-NAPHTHOQUINONES Lewis H. Sarett, Princeton, N.J., assignor to Merck & Co., Inc., Railway, N.J., a corporation of New Jersey No Drawing. Filed June 23, 1965, Ser. No. 466,464 2 Claims. (Cl. 16753.1)

trolling coccidiosis by the administration of such compounds to poultry.

Coccidiosis is a common and widespread poultry disease caused by species of protozoan parasites of the genus Eimeria. The most important of these species are E. maxima, E. acervulina, E. tenella, E. necatrix, E. brunetti, E. praecox and E. mitz's. In turkeys, E. meleagridis and E. adenoides are also causative organisms of coccidiosis. When left untreated, the disease leads to poor weight gain, reduced feed efliciency and high mortality. For these reasons, the control of coccidiosis is highly important to the poultry industry. Although E. tenella and E. necatrix cause the most lethal forms of the disease, it is known that infections due to other species, and particularly to the so-called intestinal species such as E. acervulina, E. brunelti and E. maxima, also present a serious economic problem.

It is an object of this invention to provide a new and novel method of com'batting coccidiosis. It is a further object to provide novel anticoccidial compositions. A more specific object is provision of animal feeds and feed supplement compositions containing the anticoccidial agents described herein.

In accordance with the present invention it has now been found that certain Z-aralkyl (or aralkenyl)-3-hydroxy-1,4-naphthoquinone and 2-cycloalky1-alkyl (or alkenyl)-3-hydroxy-1,4-naphthoquinone compounds are of value in controlling coccidiosis when administered in minor amounts to animals susceptible thereto. These anticoccidial substances have the structural formula where A is a divalent polymethylene radical or an unsaturated polymethylene radical and Y represents cycloalkyl, phenyl, or a para-substituted phenyl ring where the para substituent is phenoxy, phenylthio or cycloalkyl. The saturated orunsaturated polymethylene moiety attached at the 3-position of the naphthoquinone ring preferably has a chain length of 15 carbon atoms, and may be straight or branch chained. As will be clear to those skilled in this art, the moiety represented by the symbol in the above structure may be unsaturated only when the carbon-carbon chain has at least 2 carbons. In the preferred compounds this polymethylene or unsaturated polymethylene radical contains a 3-carbon straight chain which may contain branching, e.g. (CH CH=CH-CH CH-CHCH CH and the like.

The cycloalkyl radical in the anticoccidial compounds described herein may have from 3-7 carbon atoms, e.g.

cyclopropyl to cycloheptyl, although the cyclopentyl and cyclohexyl radicals are the preferred embodiments of this aspect of the invention.

Examples of naphthoquinones useful in the methods and compositions of this invention include 2-(3-cyclohexylpropyl)-3-hydroxy-1,4-naphthoquinone; 2-(3-cyclohexyl- Z-rnethylpropyl) -3-hydroxy-1,4-naphthoquinone; 2- [3-(4- phenoxyphenyl) propyl]-3-hydroxy-1,4-naphthoquinone; 2-(4-cyclohexylbutyl)-3-hydroxy 1,4 naphthoquinone; 2-[3-(4-phenoxyphenyl)-propen-1-yl] 3 hydroxy 1,4- naphthoquinone; 2-[3-(4-phenylthiophenyl) -propyl]-3-hydroXy-1,4-naphthoquinone; Z-(S-cyclopentylphenyl)-3-hydroxy 1,4 naphthoquinone; 2-[3-(4-cyclohexylphenyl)- propyl] 3 hydroxy-1,4-naphthoquinone; 2-(3-trans-decalylpropyl)-3-hydroxy-1,4-naphthoquinone; 2 (4cyclohexylbuten-Z-yl)-3-hydroxy 1,4 naphthoquinone; 2-(4- cyclohexyl-3-methylbutyl)-3-hydroxy 1,4 naphthoquinone; and 2-[2-(4-phenoxyphenyl)-ethyl]-3-hydroXy-1,4- naphthoquinone.

The preferred anticoccidial methods and compositions of the present invention are those wherein the active ingredient is a 2-(3-substituted propy1)-3-hydroXy-1,4- naphthoquinone of the formula 0 ll R1 where R represents cyclohexyl or 4-phenoxyphenyl, and R represents hydrogen or a loweralkyl group, preferably one having -14 carbon atoms such as methyl, ethyl, isopropyl and butyl.

The naphthoquinones of Formula I above are used to treat and/ or prevent coccidiosis in accordance with this invention by administering them orally to poultry. They may be given in the feedstuif of the birds, in the drinking water, or if desired by direct administration dissolved or suspended in a suitable solvent. In any case, only minor amounts are required in order to obtain the desired anticoccidial result.

It is preferred to disperse the naphthoquinone compound in the finished feed of the animals, and to administer the medicated feed ad libitum to the birds. Good anticoccidial effect is achieved with feedstufis containing from about 0.005% to 0.125% by weight of the 2-(substituted alkyl or substituted alkenyl)-3-hydroxy-1,4-naphthoquinone, with feed concentration levels of about 0.01% to 0.1% by weight being preferred, especially with the 2-[3-(4-phenoxyphenyl)-propyl]-3-hydroxy-l,4-naphthoquinones and the 2-(3-cyclohexyl)- propyl-3-hydroXy-1,4-naphthoquinones of Formula II above. Higher levels may be used, but are employed primarily for therapeutic use to treat an established infec tion, when the drug is administered only for relatively short periods of time. It might be mentioned here that dose levels of poultry coccidiostats are expressed in the art in terms of percent concentration of drug in the feed or drinking water because the exact amount of feed or water consumed by an individual bird is not measured as a matter of general practice.

The feedstutf compositions referred to herein are of the type normally used in the poultry-raising industry. They may be so-called mashes containing ground grain, protein, and mineral and vitamin concentrates. Alternatively, they may consist of broiler feeds made up primarily of corn supplemented with proteins and growth factors. In any event, the feedstutfs containing the coccidiostats of this invention are nutritionally adequate ones for the poultry.

As previously mentioned, the Z-(substituted alkyl or substituted alkenyl)-3-hydroxy-1,4-naphthoquinone may also be administered to poultry by way of the drinking water of the birds. When this route is used for prevention of coccidiosis, the treatment levels in the water are generally about one-half of those that would be used in a solid feedstufi since the birds drink about twice as much as they eat. This method of treatment is advantageously employed in the therapeutic use of the compounds since poultry infected with coccidiosis consume less solid feed than normal healthy birds. The compounds may be added directly to the drinking water, or alternatively, water-soluble powders may be prepared, in which the coccidiostat is intimately admixed with a suitable carrier, suchas dextrose or sucrose, and these powders added to the drinking water of poultry as necessary. Such watersoluble powders may contain any desired concentration of coccidiostat, and preparations containing from about 0.1-20% by weight of active compound are suitable.

Compositions which are one of the preferred features of the invention are feed supplements or pre-mixes in which the Z-(substituted -3-hydroxy-1,4-naphthoquinone compound of Formula I is present in relatively large amounts in a poultry feed additive. The carrier vehicle or diluent for such feed supplements should be essentially non-reactive with the anticoccidial agent, safely administrable to poultry, and one that is or may be a normal ingredient of the finished feed. Diluents which are normally employed are solid orally ingestible poultry feed additives such as distillers dried grains, corn meal, citrus meal, fermentation residues, wheat middlings, corn gluten feed, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits and the like. For the compositions of this invention, nutritive carriers are preferred. These supplements are incorporated in the poultry feed either directly or after an intermediate dilution or blending step.

The anticoccidial compounds described herein are intimately dispersed or blended throughout the solid orallyingestible carrier by methods such as grinding, stirring, milling or tumbling. They are normally dispersed or mixed uniformly in the diluent but in some instances may be sorbed on the carrier. The desired concentration of coccidiostat is achieved by selecting proper diluents and by altering the ratio of carrier to active ingredient. Animal feed supplement formulations containing from about to about 40% by weight, and preferably from about 30% by Weight, of naphthoquinone compound are particularly suitable for addition to poultry feeds, and are a preferred embodiment of the invention. The optimal cona large extent a function of the desired level of active ingredient in the finished feed.

The feed supplements are usually further diluted with feed ingredients such as corn meal or soybean meal before being incorporated in the animal feed. In this intermediate processing step the level of coccidiostat is reduced, thus facilitating uniform distribution of the substance in the finished feed which is a nutritionally adequate one normally containing a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.

An additional aspect of this invention comprises anticoccidial compositions of the type described hereinabove which contain one or more other coccidiostats in addition to the Z-(aralkyl or aralkenyl)-3-hydroxy-1,4-naphthoquinone or the 2-(cycloalkyl-alkyl or cycloalkylalkenyl)-3-hydroxy-l,4-naphthoquinone. Such compositions may be used when it is desired to broaden the spectrum of compositions containing only the naphthoquinone, or to improve potency against a particular strain of coccidia. Among the coccidiostats heretofore developed which may be added to compositions containing the 1,4- naphthoquinone compound of structural Formula I above there may be mentioned 2-methyl-3,5-dinitrobenzamide, nicarbazin, glycarbylamide, 3,5-dinitrobenzamide, methiotriazonine-bithionol mixtures, 1-(2-lower alkyl-4-amino-5- pyrimidinylmethyl)-2-methyl pyridinium chloride hydrochloride, 1-(2-lower alkyl4-amino-5-pyrimidiny1methyl)- 4-methyl pyridinium chloride hydrochloride, and methyl- 2-ethoxy-4-acetamido benzoate. All or any of these as well as others not given in this representative listing may be mixed with the naphthoquinones to provide highly potent coccidiostat compositions which in some instances may exhibit potency greater than would be expected from the mere additive elfective of the drugs.

The anticoccidial activity of the 2-(substituted)-3-hydroxy-l,4-naphthoquinones of Formula I against different species of coccidia is determined using straight run White Leghorn chicks. The birds, in groups of three each, are weighed and placed in cages with Wire floors. They are fed ad libitum a standard laboratory ration in which graded concentrations of test compounds are blended just prior to use. Normal and infected control birds are fed basal ration containing no test compound. On the second day of the test the chicks are inoculated orally with sporulatcd oocysts of a selected species of coccidia. On the sixth day after inoculation all surviving birds are sacrificed and weighed. Feces are collected from the preceding 24 hours, and their oocyst content determined.

In experiments carried out in this manner the following results were obtained, the figures denoting the percent concentration in feed at which the compounds were active in preventing the development of coccidiosis in birds infected with the indicated species of coccidia:

Compound E. tenellzz Emaxima E. acervulina E. brun-etti 3-11 ydr0xy-1,4-u aphthoquinone.

2-[3-(4-phenoxyphenyl)-propy1]-3- 1-4-naphthoquinone qumone 2-[3-(4 phenylthiophenyl) -propy1]- 3-hydr0xy-1,4-naphthoquinone 2-(5-cyelopentylpentyl)-3-hydroxy- 1,4-naphthoguinone 2-[3- (4-eyelohexy1phenyl) propyl]- 3-hydroxy-lA-naphthoquinone centration of coccidiostat in these feed supplements will depend to some extent on the particular compound employed. Since it is convenient for the feed manufacturer to use about 1-5 pounds of feed supplement for each ton of finished feed, the preferred concentration of any Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.

What is claimed is:

1. The method of controlling coccidiosis in poultry one of these coccidiostats in the supplement is also to that comprises orally administering to poultry an anti- 5 6 coccidially effective amount of a 1,4-naphth0quinone of References Cited the formula UNITED STATES PATENTS 2,510,487 6/1950 Waletzsky 16753.1 2,553,647 5/1951 Fieser 16753.1 A-Y 5 i on OTHER REFERENCES Y The Yearbook of Agriculture, Animal Diseases (1956),

Vet. Bulletin, vol. 16 (194-6), pp. 5-6. Dorland, The American Illustrated Medical Dictionary, 17th ed. (1938), p. 330.

where A represents a divalent saturated or unsaturated 0 polymethylene having from 1-5 carbon atoms, and Y is cycloalkyl of 5 or 6 carbon atoms, phenyl or para-substituted phenyl wherein said para substituent is phenoxy, phenylthio c-r cyclohexyl. ALBERT T. MEYERS, Primary Examiner.

2. The rriethod of controlling coccidiosis in poultry 15 JULIAN s. LEVITT, Emmineh that comprises orally administering to poultry an antiwccidially effective amount of -t -p yp y s. I. FRIEDMAN, Assistant Examiner. propyl] -3-hydroxy-l ,4-naphthoquinone. 

1. THE METHOD OF CONTROLLING COCCIDIOSIS IN POULTRY THAT COMPRISES ORALLY ADMINISTERING TO POULTRY AN ANTICOCCIDIALLY EFFECTIVE AMOUNT OF A 1,4-NAPHTQUINONE OF THE FORMULA 